A key feature of the immune system is its ability to respond quickly and specifically to previously encountered pathogens by mobilization of memory cells that were generated by an initial exposure to Ag. With the threat of bioterrorism using viral and bacterial pathogens, the critical importance of exploiting the memory response for protection of the human population against disease through vaccines has renewed immediacy. A major route of infection for agents likely to be used for bioterrorism is inhalation. Two pathogens that will be studied as part of this program that are typically transmitted by aerosol infection are influenza (flu), and tuberculosis (Tb). Both agents cause inflammation of the lung and are associated with T cell recruitment into the site to clear (flu), or limit (Tb) disease. Vaccine development to such organisms will depend upon greater understanding of the requirements for generating effector and memory cells with the capacity to migrate, respond, and persist in target tissues. We have developed adoptive transfer models with TCR transgenic CD4 and CD8 cells in which we can induce memory cells with a known history of Ag exposure and study factors that affect their function in vivo. We will study mechanisms that regulate T cell recruitment into the lungs in flu infections using genetically engineered viruses carrying epitopes for which these T cells are specific. We will collaborate with projects 1 and 2 to extend our studies to flu-specific CD4 and CD8 effector and memory subsets to investigate means to optimally induce and maintain persisting memory in the lung. We will study normal animals to validate our findings to flu and to investigate molecular pathways that regulate recruitment of CD4 cells into the lung in Tb with project 4. The goals of this proposal are to determine the adhesion pathways that regulate T cell migration into the lung, to assess the contribution of the inflammation to migration, to define memory T cell subsets that confer protection in the lung, and to evaluate the importance of memory T cells that persist in the lung for long term immunity. For this project, we will take advantage of established experimental strategies as well as novel tools that will facilitate basic studies of mechanisms that promote and modulate T cell memory to inhaled pathogens. Such information will be valuable for development of vaccination protocols that enhance efficacy through immunotherapeutic approaches to optimize protective T cell responses in the lung.